Complex regional pain syndrome (CRPS) is a syndrome, in which after a trauma such as a bone fracture or a nerve injury, pain continues with severity disproportionate to the degree of the trauma and lasts persistently. CRPS has been called various names. It is said that CRPS was originally coined by Mitchell in 1867, who described, as causalgia, burning pains after nerve injuries following bullet wounds or the like during the American Civil War. Since then, CRPS has also been called by various names such as algodystrophy, chronic traumaric edema, and painful post-traumatic osteoporosis. Then, it was proposed that stubborn burning pain and abnormal contraction and expansion of blood vessels after a trauma be originated from the sympathetic nervous system. In 1946, Evans introduced such a notion as reflex sympathetic dystrophy (RSD). After that, names such as causalgia and RSD were generally used in pain-related fields. In 1986, the International Association for the Study of Pain clearly defined RSD as one not following an obvious nerve injury, while causalgia as one following a nerve injury. Nevertheless, various controversies arose: among RSD conditions, there is a case not responding to sympathetic blocks or the like; the primary site of the disease is not clear; and so forth. In 1994, Task Force on Taxonomy of the International Association for the Study of Pain unified and defined RSD as CRPS type I and causalgia as CRPS type II up to now.
CRPS is characterized by various symptoms such as allodynia, hyperalgesia, decreased sensation, abnormal tactile sensation, change in skin color, abnormal sweating, skin contraction and pigmentation, wrinkle disappearance and glossing, nail deformation and thinning, limited range of joint movement, bone contraction, weakened muscle strength, and involuntary movement. The most distinctive feature of CRPS is the strength of the pain. The strong and persistent pain disproportionate to the degree of trauma greatly reduces the QOL of the patients. Nonetheless, the medical places where CRPS is treated are full of confusion. The main reason is that the disease has not been elucidated yet. As the conservative treatment method, various treatment methods have been attempted so far, which include: drug therapies (NSAIDS, steroids, strong and weak opioids, antianxiety drugs, anticonvulsant drugs, and the like), physical therapies (training for moving a joint in a range, muscle training, and the like), block therapies (sympathetic blocks, electrical spinal cord stimulation therapy, and the like), and surgical therapies such as neurolysis, neurectomy, and nerve grafting. However, effective treatment methods, particularly effective pharmaceutical compositions, have not been available yet until now.
Meanwhile, metallothionein (MT) is a protein having attracted attention in the central nervous system recently. The increase of this protein has been observed after brain injury and various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS. Further, MT is known to be a protein contributing neuroregeneration (NPLs 1 to 7).
Nevertheless, there have been very little findings about MT in the peripheral nervous system. There has been no report at all regarding a relation between MT and pain of CRPS or the like.